Neuroinflammation is an important constituent of many neurodegenerative diseases. In most of these diseases, neurons become stressed as a result of a toxic accumulation of substances, as in the case of sphingolipidoses (e.g. Tay-sachs Disease, Krabbe's Disease, Gaucher's Disease, Farber's Disease, Sandhoff's Disease, Niemann-Pick Disease, Fabry's Disease). The stressed neuron can then activate astrocytes or astroglia to produce inflammatory cytokines. These inflammatory cytokines, in turn, have further deleterious effects on neurons in the vicinity. The activated astrocytes and microglia can attract lymphocytes, further exacerbating the entire process (Wyss-Coray and Mucke, 2002 Neuron, 35: 419-432.)
One of the key inflammatory cytokines is interleukin-1, which is known to be a key pro-inflammatory cytokine over-expressed by activated microglia (Basu, Kraddy, and Levison, 2004 Journal of Neuroscience Research, 78(2): 151-156.). This cytokine can cause death of neurons, which will activate more microglia, and in turn more interleukin-1 will be produced so that the production of this pro-inflammatory cytokine is a self-sustaining and self-amplifying system (Griffin, 2006 American Journal of Clinical Nutrition, 83(Suppl): 470S-474S.). It has been known for some time that inflammatory cytokines are elevated in Alzheimer's and Parkinson's patients and are postulated to be major contributors to the pathogenesis of these neurological disorders (Perlmutter, 2000 Archives of Neurology, 57(6): 786-788.). Another neurological disease with a key neuroinflammatory component is amyotrophic lateral sclerosis in which motor neurons die. Recent evidence suggests that neuroinflammation and microglial cells play a key role in this neuroinflammatory disorder and in animal models of this disease (Weydt and Moller, 2005 Neuroreport, 16(6):527-531.). Parkinson's disease is another neurodegenerative disease with a key neuroinflammatory component. Brains taken from Parkinson's patients show a very conspicuous glial cell neuroinflammatory reaction, which is manifested by elevated cytokine levels and up-regulation of inflammatory-associated factors, such as cyclo-oxygenase-2 and inducible nitric-oxide synthase (Hunot and Hirsch, 2003 Annals of Neurology, 53(Suppl3): S49-S58.).
Alzheimer's disease is another important neurodegenerative condition in which chronic inflammation is very closely linked to lesioned areas of the brain. Activated microglial, cytokines, and chemokines are associated with this disease. Inflammatory mediators are locally produced and elevated in the affected regions of Alzheimer's brains (McGeer and McGeer, 2002 Journal of Neurovirol., 8(6): 529-538.). Many authors have suggested that neuroinflammation is a potential target for modifying the course of Alzheimer's disease (Hull and Hampel, 2002 Ernst Schering Res Found Workshop, (39): 159-178.).
Another important neurodegenerative disease in which neuroinflammation plays a key role is multiple sclerosis. Inflammatory mediators and activated microglial are also found in the demyelinated areas of the brain.
As mentioned previously, there are a number of other neurological diseases in which products accumulate abnormally in neurons and cause abnormal stress. In turn, the stress of the neuron can activate microglial and astrocytes, and produce an inflammatory response. These diseases include Hurler's Syndrome, Scheie's Syndrome, Hunter's Syndrome, San Fillipo's Syndrome, Maroteaux-Lany Syndrome, Sly Syndrome, Fucosidosis, Alpha-mannosidosis, Beta-mannosidosis, Schindler's Disease, Pompeii's Disease, Woman's Disease, and Infantile Neuronal Ceroid Lipofuscinosis.
Another neurodegenerative disease in which neuroinflammation is thought to play a role is autism. Recent evidence suggests that there is neuroglial activation in brain tissue and cerebrospinal fluid in patients with autism, indicating an important role for neural inflammation in autism (Pardo, Vargas, and Zimmerman, 2005 International Review of Psychiatry, 17(6): 485-495.). Other investigators have suggested that neuroinflammation increases with aging, and that this exacerbated neural inflammation can impair neuronal plasticity and lead to a heightened neuroinflammatory response in aged individuals (Godbout and Johnson, 2006 Neurologic Clinics, 24(3): 521-538.).
Finally, traumatic brain injury (TBI) is a neurodegenerative disease of importance in which neuroinflammation is a major contributor to the neuro-destructive process. Investigators have suggested that inflammation after TBI may be involved in tissue damage in sites other than the localized injury (Rooker et al., 2006 Mediators Inflammation, 2006(1): 90123). Another interesting aspect of neuroinflammation in the CNS is the recent report that the trauma-associate inflammatory response may impair embryonic stem cell survival and integration after injury (Molcanyi et al., 2007 Journal of Neurotrauma, 24(4): 625-637.). Clearly, neuroinflammation is a key component of many neurodegenerative diseases and control of this process may prevent tissue damage and promote recovery.
Autoimmune disorders are characterized by the body producing an inappropriate immune response against its own tissue. At times the immune system will cease to recognize one or more of the body's normal constituents as self and create autoantibodies that attach to its own cells, tissues and/or organs. This induces inflammation and injury and leads to autoimmune disease.
The immune system is the body's method of protection against microorganisms and other foreign substances. It is composed of two key components as well as others. One component, B-lymphocytes, specialized white blood cells, produces antibodies, proteins that attached to foreign substances and rid them from the body. The other component consists of special white blood cells called T lymphocytes, which attack foreign substances directly. The largest group of autoimmune diseases consists of T-cell-mediated autoimmune disorders including type I diabetes, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and multiple sclerosis (Tang et al. 2006 Immunol Rev. 212: 217-237). This is only a partial list, since some scientists have classified more than eighty disorders as autoimmune diseases. In these diseases, T cells, which express CD4 and CD8 surface proteins respectively, generate cytokines and cytolytic granules that directly destroy the targeted tissues. There are multiple pathways to tissue destruction. For example, the CD8+ T cells can interact directly with a target cell, such as an islet or a neuron and lyse the cell. In addition, cytokines, including TNFα also destroy tissues by triggering a suicide event, apoptosis, with the target cell. T-cells come in a number of subtypes. Since T-cells play such an important role in a number of autoimmune diseases, the regulation of T-cell activity has become an attractive therapeutic target. The products of T-cell activation, the inflammatory cytokines and chemokines such as TNF-α, IL-1, IL-6, IL-10, IL-12 and IL-17, are indicative that the regulation of these cytokines' expression will have a beneficial effect.
An expanding body of research data reveals a connection between B cells and rheumatoid arthritis and other autoimmune disorders (Dorner et al. 2003 Curr. Opin. Rheumatol 15: 246-252). Also the interaction of B cells and T-cells plays an important role in the pathogenesis of rheumatoid arthritis and other autoimmune disorders (Takemura et al. 2001 J. Immunol 107: 4710-4718). B cells produce proinflammatory cytokines such as TNFα, IL-1 and IL-6. The role of IL-6 with regard to autoimmunity has gained more importance with the recognition that IL-6 induces differentiation of B cells to antibody producing plasma cells, induces activated T cells, acts on hepatocytes to induce acute-phase reactants, including C-reactive protein (CRP) and fibrinogen, and decreases serum albumin levels.
Until recently, it was believed that there were only two types of T helper cells: TH1 and TH2. Considerable new evidence indicates that a new type of cells called TH17 helper cells may play an important role in the pathogenesis of autoimmune disease (Cua et al. 2003 Nature 421: 744-748, Murphy et al. 2003 J. Exp Med. 198: 1951-1957, Langrish et al. 2005 J. Exp Med. 201: 233-240, Chen et al. 2006 J. Clin. Invest. 116: 1317-1326). The TH17 helper cells produce a cytokine called IL-17, thought to cause late occurring inflammation by recruiting immune cells to peripheral tissues (Park et al. 2005 Nat. Immunol. 6: 1133-1141). Many lines of evidence indicate that IL-17 is a pathogenic effecter molecule in autoimmunity. IL-6 promotes the development of T-17 helper cells (Bettelli et al. 2006 Nature 441: 235-238).
The TH17 pathway involving cytokine IL-17 has emerged to be a major participant in T cell-mediated sustained tissue damage (.Steinman. L. 2007 Nature Med. 13, 139-145). The pathway involves not only IL-17 but also cytokine IL-23, a heterodimeric molecule sharing the p40 subunit of TH1 cytokine IL-12, but differs from IL-12 because of its distinctive p19 subunit. IL-23 drives a population of T-cells that produce IL-17, IL-6 and TNF (Furuzawa-Carballeda et al. 2007 Autoimmun Rev January; 6(3):169-175).
There is a body of evidence to suggest that dysregulation of T and B cell activity and response play a major role in inflammation as well as in autoimmunity. Importantly, the medicants of this invention are ribonucleotide reductase inhibitors. Ribonucleotide reductase catalyzes the reductive conversion of ribonucleotides to deoxynucleotides. This reductive reaction is a prime target for impeding cellular proliferation, and therefore amenable to controlling the quantity of T and B cells because it is a rate limiting step in the biochemical pathway leading to DNA synthesis and thus cell replication. DNA synthesis cannot occur without invoking this reaction since the endogenous pools of dNTP in mammalian cells are inadequate to support new DNA synthesis. It has been shown that rate of uncontrolled cell growth is closely associated with the specific activity of this enzyme. Members of this class of compounds have the ability to down regulate the expression of inflammatory cytokines produced by B and T cells, TNF α, IL-1, IL-6, IL-10, IL-12, and particularly IL-17. The IL-17/IL-23 pathway plays a major role in promoting and maintaining late tissue damage. Thus ribonucleotide reductase inhibitors should serve as novel therapeutic agents in treating neuroinflammatory and autoimmune disorders.